Benzoxazole compound and pharmaceutical composition containing the compound

Description

Technical Field

[0001] The present invention relates to a benzoxazole compound which selectively activates, among peroxisome proliferator-activated receptors (PPARs), PPARα, and is usefully employed as a drug for preventing and/or treating diseases including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases. The invention also relates to a pharmaceutical composition containing the compound.

Background Art

[0002] PPARs are known to be a family of nuclear receptors, and three sub-types thereof (α, γ, δ) have been already identified (Nature, 347, 645-650, 1990; Cell, 68, pp. 879-887, 1992; Cell, 97, pp. 161-163, 1999; Biochim. Biophys. Acta., 1302, pp. 93-109, 1996; and Journal of Medicinal Chemistry, 43, pp. 527-550, 2000).

[0003] Among the three sub-types, PPARα is expressed predominantly in the liver and is known to be activated by a plasticizer or a fibrate-type drug such as Wy 14643 or a commercially available pharmaceutical; e.g., clofibrate, fenofibrate, bezafibrate, or gemfibrosil (Journal of the National Cancer Institute, 90, 1702-1709, 1998, Current Opinion in Lipidology, 10, pp. 245-257, 1999).

[0004] In mammals, activation of PPARα is known to promote β oxidation of fatty acids and lower a blood triglyceride level. In humans, the total level of blood lipids including low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol decreases. Thus, a PPARα-activator is useful as a drug for preventing and/or treating a disease such as hyperlipidemia. In addition, the PPARα-activator, which increases the high-density lipoprotein (HDL) cholesterol level and, in blood vessels, suppresses expression of VCAM-1 (a type of cell adhesion molecules), is considered to be usefully employed as a drug for preventing and/or treating diseases such as arteriosclerosis. Furthermore, the PPARα-activator is considered to be usefully employed as a drug for preventing and/or treating diseases such as diabetes, inflammatory disease, and heart diseases (Journal of Atherosclerosis and Thrombosis, 3, pp. 81-89, 1996; Current Pharmaceutical Design, 3, pp. 1-14, 1997; Current Opinion in Lipidology, 10, pp. 151-159, 1999; Current Opinion in Lipidology, 10, pp. 245-257, 1999; The Lancet, 354, pp. 141-148, 1999; Journal of Medicinal Chemistry, 43, pp. 527-550, 2000; and Journal of Cardiovascular Risk, 8, pp. 195-201, 2001).

[0005] PPARγ, which is expressed predominantly in adipocytes, is known to play an important role in differentiating and proliferating adipocyte. Examples of known activators for PPARγ include thiazolidine derivative drugs such as troglitazone, pioglitazone, and rosiglitazone. These drugs are known to transform fully differentiated adipocytes having reduced insulin sensitivity into small adipocytes having high insulin sensitivity, thereby improving insulin resistance (Journal of Biological Chemistry, 270, 12953-12956, 1995; Endocrinology, 137, pp. 4189-4195, 1996; Trends Endocrinol. Metab., 10, pp. 9-13, 1999; and J. Clin. Invest., 101, pp. 1354-1361, 1998). However, PPARγ has been reported to have the adverse effects on humans of increasing the amount of fat and body weight and causing obesity (The Lancet, 349, pp. 952, 1997). Recently, it is also reported that a PPARγ antagonist possibly improves insulin resistance (Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999; The Journal of Biological Chemistry, 275, pp. 1873-1877, 2000; and J. Clin. Invest., 108, 1001-1013, 2001).

[0006] PPARδ, which is present ubiquitously in the body, is known to take part in lipid metabolism. However, only a few high-selectivity PPARδ activators have been reported, and the biological meaning of PPARδ remains unclear. At present, the structures of PPARδ activators are reported in a wide range of literature (Diabetes, 46, 1319-1327, 1997; and Journal of Medicinal Chemistry, 43, pp. 527-550, 2000). In a recent report, GW 501516, a type of PPARδ activator, elevates HDL level in monkeys (Proc. Natl. Acad. Sci., 98, pp. 5306-5311, 2001). Further, it is reported that in adipocytes and skeletal muscle cells that have expressed activated PPARδ, lipid-burning is promoted (Cell, 113, pp159-170, 2003). However, a compound F, a PPARδ activator, disclosed in WO 97/28149 exerts an unfavorable effect of accumulating lipids in human macrophages (Journal of Biological Chemistry, 276, pp. 44258-44265, 2001). In addition, results of an experiment employing PPARδ-deficient mice indicate that activation of PPARδ induces lipid accumulation action (Proc. Natl. Acad. Sci., 99, pp. 303-308, 2002). These phenomena accelerate arteriosclerosis and reduce the effect of treating arteriosclerosis. Therefore, effects of PPARδ on treatment of arteriosclerosis remain unelucidated.

[0007] As described above, a PPARα-selective activator having low activity to PPARγ and to PPARδ is expected to be useful for preventing and/or treating, without accompanying obesity or increase in body weight, diseases such as hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.

[0008] WO 94/01420 discloses the following compounds having a benzoxazole skeleton (Bioorg. Med. Chem. Lett., 6, pp. 2121-2126, 1996; and Bioorg. Med. Chem. Lett., 6, pp. 2127-2130, 1996)

[0009] WO 96/04260 discloses the following compounds (J. Pharmacol. Exp. Ther., 284, pp. 751-759, 1998).

[0010] WO 97/25042 and WO 97/31907 also disclose compounds having a benzoxazole moiety. However, these compounds do not exhibit PPARα-selective activation effect, but rather exert a strong PPARγ activation effect.

[0011] WO 02/46176 discloses compounds represented by the following formula:

(wherein each of R¹ and R² represents a hydrogen atom, a halogen atom, a nitro group, a C1 to C8 alkyl group', a C1 to C8 alkoxy group, or a C6 to C10 aryl group, or R¹ and R², together with the carbon atoms to which they are attached, may form a benzene ring; X represents an oxygen atom, a sulfur atom, -NR⁰- (R⁰ represents a hydrogen atom or a C1 to C8 alkyl group), or -CH=CH-; G represents a single bond or a carbonyl group; R³ represents a C1 to C8 alkyl group, a C2 to C8 alkenyl group, a C2 to C8 alkyl group, a C3 to C7 cycloalkyl group, a C1 to C8 alkyl group substituted by a C3 to C7 cycloalkyl group, a C6 to C10 aryl group, an arylalkyl group (formed of a C6 to C10 aryl moiety and a C1 to C8 alkyl moiety), a heterocyclic group, or a heterocyclicalkyl group (containing a C1 to C8 alkyl moiety); n is an integer of 0 to 5; Y represents -CH₂-, a carbonyl group, or -CH=CH-; Z represents an oxygen atom or a sulfur atom; p represents an integer of 0 to 5; each of R⁴ and R⁵ represents a hydrogen atom or a C1 to C8 alkyl group; and W represents a carboxyl group, a C2 to C8 alkoxycarbonyl group, a sulfonic acid group, a phosphonic acid group, a cyano group, or a tetrazolyl group).

[0012] However, WO 02/46176 provides a specific description only in terms of thiazole compounds (X in the above formula is a sulfur atom), and no specific description is provided in terms of benzoxazole compounds. The specification discloses activation effect on each sub-type of PPARs. The disclosed compounds activate all sub-types of PPARα, PPARγ, and PPARδ, and thus are not regarded as PPARα-selective activators.

[0013] WO 03/074495, published after the priority date of the present patent, relates to human PPAR activators, pharmaceutical compositions thereof, and to methods of treatment of diseases mediated by one or more human PPARα, PPARγ or PPARδ.

Disclosure of the Invention

[0014] The present inventors have carried out extensive studies in order to find a compound which selectively activates PPARα among other PPARs, and have found that a benzoxazole compound represented by the following formula (1) selectively activates PPAR alpha and is useful as a drug for preventing and/or treating, without accompanying obesity or increase in body weight, diseases including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.

[0015] Accordingly, the present invention provides the compounds, or a salt thereof, defined in claim 1. Also provided is an agent for selectively activating PPARα as defined in claim 2.

[0016] Also described herein is a benzoxazole compound represented by the following formula (1):

(wherein R¹ represents a hydrogen atom, a C_1-8 alkyl group, a C_3-8 alkenyl group, a C_3-8 alkynyl group, a C_3-7 cycloalkyl group, a C_3-7 cycloalkyl-C_1-8 alkyl group, a C_6-10 aryl-C_1-8 alkyl group (the C_6-10 aryl moiety may have one or two substituents selected from a halogen atom, a hydroxyl group, a nitro group, an amino group, a di-C_1-4 alkylamino group, a C_1-4 alkyl group, a C_1-4 alkoxy group, a benzyloxy group, a phenylsulfonylmethyl group, and a C_1-4 alkanesulfonyloxy group), a pyridyl-C_1-8 alkyl group, a C_1-8 alkoxycarbonyl-C_1-8 alkyl group, or a carboxy-C_1-9 alkyl group; R² and R³ may be the same or different and represent a hydrogen atom, a methyl group, or an ethyl group; and n represents a number of 1 to 3) or a salt thereof.

[0017] Also described is a pharmaceutical composition containing a benzoxazole compound represented by the above formula (1) or a salt thereof and a pharmaceutically acceptable carrier.

[0018] Also described is a medicine containing the above formula (1) or salt thereof as an active ingredient.

[0019] Also described is a remedy for hyperlipidemia containing the above formula (1) or salt thereof as an active ingredient.

[0020] Also described is a remedy for arteriosclerosis containing the above formula (1) or salt thereof as an active ingredient.

[0021] Also described is a remedy for diabetes containing the above formula (1) or salt thereof as an active ingredient.

[0022] Also described is a remedy for complications of diabetes containing the above formula (1) or salt thereof as an active ingredient.

[0023] Also described is a remedy for inflammation containing the above formula (1) or salt thereof as an active ingredient.

[0024] Also described is a remedy for heart disease containing the above formula (1) or salt thereof as an active ingredient.

[0025] Also described is a use, for producing a medicine, of a compound represented by the above formula (1) or a salt thereof.

[0026] The compounds of the present invention exert an effect of selectively activating PPARα among other PPARs, and are usefully employed as a drug for preventing and/or treating, without accompanying obesity or increase in body weight, diseases including hyperlipidemia, arterisclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.

Brief Description of the Drawing

[0027] 

Fig. 1 is a chart showing the activation factor of compound of Example 1 to PPAR isoforms.

Fig. 2 is a chart showing the activation factor of compound A to PPAR isoforms.

Fig. 3 is a chart showing the activation factor of compound B to PPAR isoforms.

Fig. 4 is a chart showing the activation factor of compound C to PPAR isoforms.

[0028] In formula (1), the C_1-8 alkyl groups represented by R¹ include linear or branched alkyl groups. Examples of these groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, and n-octyl. Of these, the following are particularly preferred: ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, and n-octyl.

[0029] The C_3-8 alkenyl groups represented by R¹ include linear or branched alkenyl groups. Examples of these groups include allyl, butenyl, pentenyl, and hexenyl, with hexenyl being particularly preferred.

[0030] The C_3-8 alkynyl groups represented by R¹ include linear or branched alkynyl groups. Examples of these groups include propargyl and butynyl, with butynyl being particularly preferred.

[0031] The C_3-1 cycloalkyl groups represented by R¹ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, with cyclohexyl being particularly preferred.

[0032] Of the C_3-7 cycloalkyl-C_1-8 alkyl groups represented by R¹, C_3-7 cycloalkyl-C_1-4 alkyl are preferred. Specific examples of these groups include cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl.

[0033] Of the C_6-10 aryl-C_1-8 alkyl groups represented by R¹, C_6-10 aryl-C_1-4 alkyl are preferred, and phenyl-C_1-4 alkyl and naphthyl-C_1-4 alkyl are more preferred. Specific examples of these groups include benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, and naphthylpropyl, with phenyl-C_1-4 alkyl being more preferred, and benzyl being particularly preferred.

[0034] The C_6-10 aryl moieties of the C_6-10 aryl-C_1-9 alkyl groups may have one or two substituents selected from halogen atoms, a hydroxy group, a nitro group, an amino group, di-C_1-4 alkylamino groups, C_1-4 alkyl groups, C_1-4 alkoxy groups, a benzyloxy group, a phenylsulfonylmethyl group, and C_1-4 alkanesulfonyloxy groups. Examples of the halogen atoms include chlorine, bromine, and fluorine. Examples of the di-C_1-4 alkylamino groups include dimethylamino, diethylamino, and diisopropylamino. Examples of the C_1-4 alkyl groups include methyl, ethyl, and isopropyl. Examples of the C_1-4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy. Examples of the C_1-4 alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, and propanesulfonyloxy. Of the listed substituents of the aryl moieties, one or two substituents selected from halogen atoms, a nitro group, and di-C_1-4 alkylamino groups are more preferred; halogen atoms are still more preferred; and chlorine atom is particularly preferred.

[0035] The pyridyl-C_1-8 alkyl groups represented by R¹ are preferably pyridyl-C_1-4 alkyl groups. Specific examples of these groups include pyridylmethyl, pyridylethyl, and pyridylpropyl. The C_1-8 alkoxycarbonyl-C_1-8 alkyl groups represented by R¹ are preferably C_1-4 alkoxycarbonyl-C_1-4 alkyl groups. Specific examples of these groups include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, methoxycarbonylethyl, and ethoxycarbonylethyl. The carboxy-C_1-8 alkyl groups represented by R¹ are preferably carboxy-C_1-4 alkyl groups. Specific examples of these groups include carboxymethyl and carboxyethyl.

[0036] In relation to R² and R³, the following cases are preferred: they are both hydrogen atoms; they are both methyl groups; one is a methyl group and the other is a hydrogen atom; or one is an ethyl group and the other is a hydrogen atom. Of these, the case where they are both methyl groups is particularly preferred.

[0037] In formula (1), preferably, R¹ is a C_1-8 alkyl group, a C_3-8 alkynyl group, or a C_6-10 aryl-C_1-8 alkyl group (wherein the C_6-10 aryl moiety may have one or two substituents selected from halogen atoms, a hydroxy group, a nitro group, an amino group, di-C_1-4 alkylamino groups, C_1-4 alkyl groups, C_1-4 alkoxy groups, a benzyloxy group, a phenylsulfonylmethyl group, and C_1-4 alkanesulfonyloxy groups).

[0038] More preferably, R¹ is a C_1-8 alkyl group, a C_3-8 alkynyl group, or a C_6-10 aryl-C_1-4 alkyl group (wherein the C_6-10 aryl moiety may have one or two substituents selected from halogen atoms, nitro group, and di-C_1-4 alkylamino groups).

[0039] Particularly preferably, R¹ is an ethyl group, an n-propyl group, an isopropyl group, an n-heptyl group, an n-octyl group, a butynyl group, a chlorobenzyl group, a nitrobenzyl group, a dimethylaminobenzyl group, a phenylpropyl group, a chlorophenylpropyl group, and a naphthylmethyl group.

[0040] Examples of the salts of the compounds of the present invention include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic base salts such as ammonium salts and trialkylamine salts; mineral acid salts such as hydrochloric acid salts and sulfuric acid salts; and organic acid salts such as acetic acid salts.

[0041] The compound of the present invention may include a solvate such as a hydrate or a geometrical (cis, trans) isomer or an optical isomer. These isomers also fall within the scope of the present invention.

[0042] Compounds of the present invention exhibiting high PPAα selectivity are the following compounds or salts thereof:

2-[4-[[N-(benzoxazol-2-yl)-N-(naphth-1-ylmethyl)]aminomethyl]phenoxy]-2-methylpropionic acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl]phenoxy]butyric acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophenyl)propyl)]aminomethyl]phenoxy]butyric acid,

2-[3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]butyric acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophenyl)propyl)]aminomethyl]phenoxy]propionic acid,

2-[3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]propionic acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl]phenoxy]propionic acid, and

2-[3-[3-[N-(benzoxazol-2-yl)-N-(2-butynyl)]aminopropyl]phenoxy]-2-methylpropionic acid,

[0043] The compounds of the present invention can be obtained in accordance with, for example, the following production methods described in reaction schemes A, D, E, F and G (in the following schemes, R¹, R², and R³ have the same meanings as described above; each of R⁴, R⁵, and R⁶ represents a C1-6 linear or branched alkyl group; and X represents a halogen atom such as fluorine, chlorine, bromine, or iodine).

[0044] The first step is achieved as follows. A phenol compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran (THF), dioxane, or acetonitrile. A necessary amount of an inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such as triethylamine or diisopropylethylamine is added thereto. Further, a necessary amount of a 2-haloalkanoic acid ester such as 2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added, and the resultant mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours. The ester is appropriately selected from among tert-butyl esters, ethyl esters, methyl esters, etc.

[0045] In the second step, the aldehyde compound is dissolved in a solvent such as 1,2-dichloroethane, dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. Subsequently, necessary amounts of a suitably selected amine compound and acid such as acetic acid are added, followed by reduction with a reductant such as sodium (triacetoxy)borohydride (NaBH(OAc)₃). When the reaction mixture is under cooling or at room temperature for several to 24 hours (under inert gas atmosphere, if necessary), the reaction is completed.

[0046] The third step is accomplished as follows. The starting amino compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. 2-Halobenzoxazole such as 2-chlorobenzoxazole is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours (under inert gas atmosphere, if necessary).

[0047] The fourth step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or THF; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0048] The first step is achieved as follows. A trialkylphosphonoacetate such as triethylphosphonoacetate is reacted with a base such as sodium hydride under cooling in a solvent such as tetrahydrofuran (THF) or dioxane. Subsequently, a starting aldehyde compound, which has been protected as required, is added thereto. The mixture is allowed to react for several to 24 hours at a temperature between ice-cooling and room temperature.

[0049] The second step is achieved as follows. The starting α,β-unsaturated carboxylate is dissolved in a solvent such as alcohol or an acetic acid ester. In the presence of a catalyst such as palladium-carbon, the solution is subjected to catalytic reduction in a hydrogen atmosphere or in the presence of a hydrogen-donating reagent such as formic acid.

[0050] The third step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or THF; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0051] The fourth step is achieved as follows. The starting carboxylic acid is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, or dichloromethane. The solution is reacted with alkyl chloro carbonate such as ethyl chloro carbonate in the presence of a necessary amount of an inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such as triethylamine or diisopropylethylamine, to thereby produce a mixed acid anhydride. Subsequently, a reductant such as sodium borohydride or an aqueous solution thereof is added thereto. The mixture is stirred for several to 24 hours at a temperature between ice-cooling and room temperature.

[0052] The fifth step is achieved as follows. In the case where an alkylsulfonate such as methanesulfonate or an arylsulfonate such as benzenesulfonate is produced, the starting alcohol compound is dissolved in a solvent such as tetrahydrofuran, dioxane, dichloromethane, or acetonitrile; alkylsulfonyl chloride (e.g., methanesulfonyl chloride), benzenesulfonyl chloride, or p-bromobenzenesulfonyl chloride is added thereto in the presence of a necessary amount of an inorganic base (K₂CO₃, Na₂CO₃, or Cs₂CO₃) or an organic base (triethylamine or diisopropylethylamine); and the mixture is stirred at a temperature between ice-cooling and room temperature for several to 24 hours. Alternatively, in the case where a halogenated compound is produced, the starting alcohol compound is dissolved in the above-described solvent; a necessary amount of triphenylphosphine and carbon tetrahalide are added thereto; and the mixture is stirred at a temperature between ice-cooling and room temperature for several to 24 hours.

[0053] The sixth step is achieved as follows. The starting sulfonate compound or halogen compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. Potassium phthalimide is added thereto, and the mixture is heated and allowed to react at a temperature between room temperature and around the boiling point of the solvent for several to 24 hours.

[0054] The seventh step is achieved as follows. The phthalimide compound is dissolved in a solvent such as ethanol, methanol, tetrahydrofuran, or dioxane. Hydrazine is added thereto, and the mixture is heated and allowed to react at a temperature between room temperature and around the boiling point of the solvent for several to 24 hours.

[0055] The eighth step is accomplished as follows. The starting amino compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. 2-Halobenzoxazole such as 2-chlorobenzoxazole is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours (under inert gas atmosphere, if necessary).

[0056] The ninth step is accomplished as follows. The starting amino compound is dissolved in an inert solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. A suitably selected halogenated compound is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours.

[0057] The tenth step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or tetrahydrofuran; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0058] The first step is achieved as follows. A starting carboxylic acid compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran (THF), dioxane, acetonitrile, or a mixture of solvents suitably selected therefrom. Oxalyl chloride is added thereto under cooling, and the resultant mixture is stirred at room temperature for several minutes to three hours. Subsequently, an amine, suitably selected, is added thereto under cooling, and the mixture is heated and allowed to react at a temperature between room temperature and around the boiling point of the solvent for several to 24 hours. After completion of reaction, the obtained compound is purified through a method known per se, and the resultant compound is further purified by means of, for example, chromatography, according to needs. Alternatively, a starting carboxylic acid and an amine, suitably selected, are dissolved in the above-described solvent, and a necessary amount of coupling reagent such as dicyclohexylcarbodiimide or WSC/HCl is added thereto under cooling. Further, HOBt, dimethylaminopyridine, or an analogous compound is added thereto, as needed. The resultant mixture is heated and allowed to react at a temperature between room temperature and around the boiling point of the solvent for several to 24 hours.

[0059] The second step is achieved as follows. A phenol compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. A necessary amount of an inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such as triethylamine or diisopropylethylamine is added thereto. Further, a necessary amount of a 2-haloalkanoic acid ester such as 2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added, and the resultant mixture is stirred at room temperature or under heating at a temperature around the boiling point of the solvent for several to 24 hours. The ester is appropriately selected from among tert-butyl esters, ethyl esters, methyl esters, etc.

[0060] In the third step, the starting amide compound is dissolved in a solvent such as tetrahydrofuran or dioxane. Subsequently, in an inert gas atmosphere, if necessary, a necessary amount of a reductant such as borane-tetrahydrofuran complex (BH₃·THF) is added thereto, and the reaction mixture is stirred at room temperature or under heating for several to 24 hours, to thereby complete the reaction.

[0061] The fourth step is accomplished as follows. The starting amino compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. 2-Halobenzoxazole such as 2-chlorobenzoxazole is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours (under inert gas atmosphere, if necessary).

[0062] The fifth step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or tetrahydrofuran; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0063] The first step is achieved as follows. A phenol compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran (THF), dioxane, or acetonitrile. A necessary amount of an inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such as triethylamine or diisopropylethylamine is added thereto. Further, a necessary amount of a 2-haloalkanoic acid ester such as 2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added, and the resultant mixture is stirred at room temperature or under heating at a temperature around the boiling point of the solvent for several to 24 hours. The ester is appropriately selected from among tert-butyl esters, ethyl esters, methyl esters, etc.

[0064] The second step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or tetrahydrofuran; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0065] The third step is accomplished as follows. The starting carboxylic acid compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile. Allyl halide such as allyl bromide or allyl iodide is added dropwise thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours.

[0066] The fourth step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or tetrahydrofuran; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0067] In the fifth step, the starting carboxylic acid and a necessary amount of triphenylphosphine are dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile, and a Wang resin is added thereto. Diethyl azodicarboxylate is added thereto under ice-cooling, and the mixture is allowed to react at a temperature between ice-cooling and room temperature for several to 24 hours. After completion of reaction, the resin is collected through filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried. Subsequently, the resin is allowed to swell in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile. An acid anhydride such as acetic anhydride is added thereto in the presence of an organic base such as triethylamine or diisopropylethylamine. The mixture is subjected to a capping reaction under ice-cooling or room temperature. After completion of reaction, the resin is collected trough filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried. The reaction is preferably performed under inert gas atmosphere.

[0068] In the sixth step, a necessary amount of triphenylphosphine is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile, and the resin prepared in the fifth step is added thereto. Moreover, a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0.1-100% equivalents) and an organic base such as piperidine are added thereto, and the mixture is allowed to react under cooling or at room temperature for several to 24 hours. The resin is collected through filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried. The reaction is preferably performed under inert gas atmosphere.

[0069] In the seventh step, the resin prepared in the sixth step is added to a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile, and then a necessary amount of HOBt, dimethylaminopyridine, or an analogous compound is added thereto. A primary amine, suitably selected, and an organic base such as triethylamine or diisopropylethylamine are added thereto, and, finally, a coupling reagent such as diisopropylcarbodiimide is added thereto. The mixture is allowed to react under ice-cooling or at room temperature for several to 24 hours. After completion of reaction, the resin is collected through filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried.

[0070] In the eighth step, the resin prepared in the seventh step is reacted with a reduction agent such as borane-tetrahydrofuran complex (BH₃·THF) in a solvent such as tetrahydrofuran or dioxane under inert gas atmosphere. The reaction is performed at room temperature or under heating at a temperature around the boiling point of the solvent under stirring for several to 24 hours. After completion of reaction, the resin is collected through filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried.

[0071] In the ninth step, the resin prepared in the eighth step is added to a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, or acetonitrile. Subsequently, 2-halobenzoxazole such as 2-chlorobenzoxazole is added thereto, and the mixture is stirred in the presence of an organic base such as triethylamine or diisopropylethylamine at a temperature between room temperature and around the boiling point of the solvent for several to 24 hours. After completion of reaction, the resin is collected through filtration, washed with a solvent suitably selected from among dimethylformamide, dichloromethane, methanol, diethyl ether, and analogous solvents, and dried.

[0072] The tenth step is achieved as follows. A solvent such as dichloromethane or chloroform is added to the resin prepared in the ninth step, and then an acid such as trifuloroacetic acid is added thereto. The mixture is stirred under cooling or at room temperature for several to 24 hours.

(Left blank)

[0073] 

[0074] The first step is achieved as follows. A starting carboxylic acid compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran (THF), dioxane, acetonitrile, or a mixture of solvents suitably selected therefrom. A necessary amount of an inorganic base (e.g., potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃)) or an organic base (e.g., triethylamine, diisopropylethylamine, or pyridine) is added thereto. Subsequently, an anhydride such as di-tert-butyl dicarbonate is added thereto, and the mixture is stirred under cooling or at room temperature for several minutes to three hours. Thereafter, ammonia or an ammonium salt such as ammonium hydrogencarbonate is added thereto, and the mixture is stirred under cooling or at room temperature for several to 24 hours. After completion of reaction, the obtained compound is purified through a method known per se, and the resultant compound is further purified through, for example, chromatography, as needed.

[0075] The second step is achieved as follows. The amide compound prepared in the first step is dissolved in a solvent such as dichloromethane, chloroform, or chlorobenzene, if necessary. Thereafter, a Lewis acid such as boron tribromide or aluminum chloride is added thereto, and the mixture is stirred at a temperature between under cooling and around the boiling point of the solvent for several to 24 hours.

[0076] The third step is achieved as follows. A phenol compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. A necessary amount of an inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such as triethylamine or diisopropylethylamine is added thereto. Further, a necessary amount of a 2-haloalkanoic acid ester such as 2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added, and the resultant mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours. The ester is appropriately selected from among tert-butyl esters, ethyl esters, methyl esters, etc.

[0077] In the fourth step, the starting amide compound is dissolved in a solvent such as tetrahydrofuran or dioxane. Subsequently, under inert gas atmosphere, if necessary, a necessary amount of a reductant such as borane-tetrahydrofuran complex (BH₃·THF) is added thereto, and the reaction mixture is stirred at room temperature or under heating for several to 24 hours, to thereby complete the reaction.

[0078] The fifth step is accomplished as follows. The starting amino compound is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. 2-Halobenzoxazole such as 2-chlorobenzoxazole is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours (under inert gas atmosphere, if necessary).

[0079] The sixth step is accomplished as follows. The starting amino compound is dissolved in an inert solvent such as dimethylformamide, tetrahydrofuran, dioxane, or acetonitrile. A suitably selected halogenated compound is added thereto in the presence of a necessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine or diisopropylethylamine. The mixture is heated at a temperature between room temperature and around the boiling point of the solvent under stirring for several to 24 hours.

[0080] The seventh step is accomplished as follows. In the case where a methyl ester, ethyl ester, or any ester that is easily hydrolyzed by an alkali is used in the first step, the resultant ester compound, serving as the starting compound of the first step, is dissolved in a solvent such as methanol, ethanol, or tetrahydrofuran; a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or an aqueous solution thereof is added thereto; and the mixture is allowed to react for several to 24 hours under cooling or heating at a temperature between room temperature and around the boiling point of the solvent. After reaction, the reaction mixture is acidified by use of an acid such as hydrochloric acid. On the other hand, in the case where a tert-butyl ester or any ester that is easily decomposed by an acid is used in the first step, the resultant ester compound is dissolved in a solvent such as dichloromethane or chloroform, then, an acid such as trifluoroacetic acid is added, and the resultant mixture is stirred for several to 24 hours under cooling or at room temperature.

[0081] The compounds according to the present invention can be produced through any of the aforementioned methods. The thus-obtained products may be purified in accordance with needs through a customary purification method such as recrystallization or column chromatography. The compounds may be converted to the aforementioned desired salts or solvates through a routine process, in accordance with needs.

[0082] As described in relation to the below-mentioned Test Example, the thus-produced compounds of the present invention exert a selective activation effect on PPARα. Thus, these compounds are usefully employed as a drug for preventing and/or treating diseases of mammals (including humans) such as hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes (e.g., diabetic nephropathy), inflammation, and heart diseases, without accompanying increase in body weight or obesity.

[0083] The pharmaceutical contains, as an active ingredient, the compound (1) or a salt thereof. No particular limitation is imposed on the form of administration, and the administration form can be appropriately determined in accordance with the purpose of treatment, and selected from among, for examples, peroral solid forms, peroral liquid forms, injections, suppositories, external preparations, ophthalmic solutions, nasal drops, ear drops, and patches. These administration forms can be produced by mixing the active ingredient with a pharmaceutically acceptable carrier and through any preparation methods known in the art.

[0084] When an oral solid drug product is prepared, the present compound (1) is mixed with a diluent (and, if necessary, an additive such as a binder, a disintegrant, a lubricant, a coloring agent, a sweetening agent, or a flavoring agent), and the resultant mixture is processed through a routine method, to thereby produce an oral solid drug product such as tablets, granules, powder, or capsules. Such an additive may be an additive generally employed in the art. Examples of the diluent include lactose, sodium chloride, glucose, starch, microcrystalline cellulose, and silicic acid; examples of the binder include water, ethanol, propanol, simple syrup, liquefied gelatin, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinyl pyrrolidone; examples of the disintegrant include agar powder, sodium hydrogencarbonate, sodium lauryl sulfate, and monoglyceryl stearate; examples of the lubricant include purified talc, stearate salt, borax, and polyethylene glycol; examples of the coloring agent include β-carotene, yellow iron sesquioxide, and caramel; and examples of the sweetening agent include saccharose and orange peel.

[0085] When an oral liquid drug product is prepared, the present compound (1) is mixed with an additive such as a sweetening agent, a buffer, a stabilizer, or a preservative, and the resultant mixture is processed through a routine method, to thereby produce an oral liquid drug product such as solution medicine, syrup, or elixir. Such an additive may be an additive generally employed in the art. Examples of the sweetening agent include saccharose; examples of the buffer include sodium citrate; examples of the stabilizer include tragacanth; and examples of the preservative include p-hydroxybenzoate ester.

[0086] When an injection is prepared, the present compound (1) is mixed with an additive such as a pH regulator, a stabilizer, or an isotonicity agent, and the resultant mixture is processed through a routine method, to thereby produce an injection such as a subcutaneous injection, an intramuscular injection, or an intraveneous injection. Such an additive may be an additive generally employed in the art. Examples of the pH regulator include sodium phosphate; examples of the stabilizer include sodium pyrosulfite; and examples of the isotonicity agent include sodium chloride.

[0087] When a suppository is prepared, the present compound (1) is mixed with an additive such as a carrier or a surfactant, and the resultant mixture is processed through a routine method, to thereby produce a suppository. Such an additive may be an additive generally employed in the art. Examples of the carrier include polyethylene glycol and hard fat, and examples of the surfactant include polysorbate 80.

[0088] When an external drug product is prepared, the present compound (1) is mixed with an additive such as a base, a water-soluble polymer, a solvent, a surfactant, or a preservative, and the resultant mixture is processed through a routine method, to thereby produce an external preparation such as liquids and solutions, creams, gels, or ointments. Examples of the base include liquid paraffin, white Vaseline, and purified hydrous lanolin; examples of the water soluble polymer include carboxyvinyl polymer; examples of the solvent include glycerol and water; examples of the surfactant include polyoxyethylene fatty acid ester; and examples of the preservative include p-hydroxybenzoate.

[0089] When an ophthalmic solution is prepared, the present compound (1) is mixed with an additive such as a pH regulator, a stabilizer, an isotonicity agent, or a preservative, and the resultant mixture is processed through a routine method, to thereby produce an ophthalmic solution. Such an additive may be an additive generally employed in the art. Examples of the pH regulator include sodium phosphate; examples of the stabilizer include sodium pyrosulfite and EDTA; examples of the isotonicity agent include sodium chloride; and examples of the preservative include chlorobutanol.

[0090] When a nasal drop is prepared, the present compound (1) is mixed with an additive such as a pH regulator, a stabilizer, an isotonicity agent, or a preservative, and the resultant mixture is processed through a routine method, to thereby produce a nasal drop. Such an additive may be an additive generally employed in the art. Examples of the pH regulator include sodium phosphate; examples of the stabilizer include sodium pyrosulfite and EDTA; examples of the isotonicity agent include sodium chloride; and examples of the preservative include benzalkonium chloride.

[0091] When an ear drop is prepared, the present compound (1) is mixed with an additive such as a pH regulator, a buffer, a stabilizer, an isotonicity agent, or a preservative, and the resultant mixture is processed through a routine method, to thereby produce an ear drop. Such an additive may be an additive generally employed in the art. Examples of the pH regulator and the buffer include sodium phosphate; examples of the stabilizer include sodium pyrosulfite and EDTA; examples of the isotonicity agent include sodium chloride; and examples of the preservative include benzalkonium chloride.

[0092] When a patch is prepared, the present compound (1) is mixed with an additive such as a tackfier, a solvent, a cross linking agent, or a surfactant, and the resultant mixture is processed through a routine method, to thereby produce a patch such as hydrated patches or cataplasms. Such an additive may be an additive generally employed in the art. Examples of the tackfier include partially neutralized poly(acrylic acid), sodium polyacrylate, poly(2-ethylhexylacrylate), and styrene-isoprene-styrene block copolymer; examples of the solvent include glycerol and water; examples of the cross linking agent include dihydroxyaluminum aminoacetate and dried aluminum hydroxide gel; and examples of the surfactant include polyoxyethylene fatty acid ester.

[0093] The dose of the drug of the present invention differs depending on the age, body weight, and condition of the patient and the manner and frequency of administration, etc. Generally, for an dult, a dose of the present compound (1) is preferably 1 to 1,000 mg, and the drug is preferably administered perorally or parenterally once a day or several times a day in a divided manner.

Examples

[0094] The present invention will next be described in detail by way of examples. All examples except Examples 12, 55, 56, 59, 63, 69, 70 and 121 are reference examples.

Production Example 1

Synthesis of ethyl 2-(3-formylphenoxy)-2-methylpropionate

[0095] 

[0096] 3-Hydroxybenzaldehyde (30.0 g, 0.246 mol) was dissolved in dimethylformamide (20 mL). Subsequently, potassium carbonate (51.00 g, 0.369 mol), and then ethyl 2-bromoisobutyrate (144.00 g, 0.737 mol) were added thereto, and the resultant mixture was stirred overnight at 80°C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate = 5/1), whereby a colorless oil was obtained (57.70 g, 0.244 mol, 99.3%).
¹H-NMR (400 MHz, CDCl₃) δ: 1.25 (t, J = 7 Hz, 3H), 1.56 (s, 6H), 4.21 (q, J = 7 Hz, 2H), 7.14 (dd, J = 8, 2 Hz, 1H), 7.32 (m, 1H), 7.41 (t, J = 8 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 9.94 (s, 1H).

Production Example 2

Synthesis of ethyl 2-[3-[N-(4-chlorobenzyl)aminomethyl]phenoxy]-2-methylpropionate

[0097] 

[0098] Ethyl 2-(3-formylphenoxy)-2-methylpropionate (25 g, 105.8 mmol) was dissolved in 1,2-dichloroethane (300 mL). Subsequently, 4-chlorobenzylamine (15.44 mL, 127.0 mmol) and acetic acid (7.26 mL, 127.0 mmol) were added thereto, and the resultant mixture was stirred for 20 minutes at 0°C. Subsequently, sodium (triacetoxy)borohydride [NaBH(OAc)₃ (26.91 g, 127.0 mmol)] was added thereto, and the mixture was stirred for five hours at room temperature. After completion of reaction, chloroform was added. Washing was performed sequentially with aqueous saturated sodium bicarbonate, water, and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol = 10/1), whereby a yellow oil was obtained (35.27 g, 92%).
¹H-NMR (400 MHz, CDCl₃) δ: 1.23 (t, J = 7 Hz, 3H), 1.59 (s, 6H), 3.72 (s, 2H), 3.74 (s, 2H), 4.24 (q, J = 7 Hz, 2H), 6.73 (d, J = 8 Hz, 1H), 6.86 (s, 1H), 6.93 (d, J = 8 Hz, 1H) , 7.18 (t, J = 8 Hz, 1H), 7.28 (m, 4H).

Production Example 3

Synthesis of ethyl 2-[3-[[N-(benzoxazol-2-yl)-N-(4-chlorobenzyl)]aminomethyl]phenoxy]-2-methylpropionate

[0099] 

[0100] Ethyl 2-[3-[N-(4-chlorobenzyl)aminomethyl]phenoxy]-2-methylpropionate (17.22 g, 47.59 mmol) was dissolved in dimethylformamide (300 mL). Subsequently, 2-chlorobenzoxazole (7.06 mL, 61.86 mmol) and diisopropylethylamine (12.4 mL, 71.38 mmol) were added thereto, and the mixture was stirred overnight at 50°C. After completion of reaction, ethyl acetate was added. Washing was performed with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate = 10/1), whereby a yellow oil was obtained (19.13 g, 84%).
¹H-NMR (400 MHz, CDCl₃) δ: 1.17 (t, J = 7 Hz, 3H), 1.57 (s, 6H), 4.15 (q, J = 7 Hz, 2H), 4.62 (s, 2H), 4.66 (s, 2H), 6.76 (m, 2H), 6.85 (d, J = 8 Hz, 1H) , 7.05 (t, J = 8 Hz, 1H), 7.21 (m, 4H), 7.28 (m, 3H), 7.41 (d, J= 8 Hz, 1H).

Example 1

Synthesis of 2-[3-[[N-(benzoxazol-2-yl)-N-(4-chlorobenzyl)]aminomethyl]phenoxy]-2-methylpropionic acid

[0101] 

[0102] Ethyl 2-[3-[[N-(benzoxazol-2-yl)-N-(4-chlorobenzyl)]aminomethyl]phenoxy]-2-methylpropionate (2.0 g, 4.18 mmol) was dissolved in ethanol (30 mL). Subsequently, an aqueous 2M sodium hydroxide solution (30 mL) was added thereto, and the mixture was stirred for one hour at 80°C. After completion of reaction, the reaction mixture was concentrated under reduced pressure, and the resultant concentrate was acidified with hydrochloric acid under ice-cooling. Chloroform was added for extraction. The chloroform layer was washed with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol = 10/1), whereby a colorless amorphous was obtained (1.50 g, 80%).
¹H-NMR (400 MHz, CDCl₃) δ: 1.57 (s, 6H), 4.60 (s, 2H) , 4.63 (s, 2H), 6.85 (m, 2H), 6.91 (d, J = 8 Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 7.18 (m, 4H), 7.28 (m, 3H), 7.40 (d, J = 8 Hz, 1H).

Synthesis of sodium 2-[3-[[N-(benzoxazol-2-yl)-N-(4-chlorobenzyl)]aminomethyl]phenoxy]-2-methylpropionate

[0103] 

[0104] 2-[3-[[N-(Benzoxazol-2-yl)-N-(4-chlorobenzyl)]aminomethyl]phenoxy]-2-methylpropionic acid (4.82 g, 10.68 mmol) was dissolved in methanol (50 mL). Subsequently, sodium methoxide (555 mg, 10.68 mmol) was added thereto, and the mixture was stirred at room temperature. After two hours, the reaction mixture was subjected to filtration and concentration under reduced pressure, whereby a yellow amorphous was obtained (4.97 g, 98%).
¹H-NMR (900 MHz, CDCl₃) δ: 1.25 (s, 6H) , 4. 51 (s, 2H) , 4.58 (s, 2H), 6.73 (m, 3H), 7.02 (m, 2H), 7.12 (m, 3H), 7.25 (m, 3H), 7.34 (d, J = 8 Hz, 1H).

[0105] In a manner similar to that described in Example 1, the compounds of Examples : 6, 12, 29, 41, 46, 48, 55, 56, 59, 63, 69, 70 and 74 were synthesized.

Example 6

2-[3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]-2-methylpropionic acid

[0106] 

[0107] MS(m/z)438(M⁺)

Example 12

2-[4-[[N-(Benzoxazol-2-yl)-N-(naphth-1-ylmethyl)]aminomethyl]phenoxy]-2-methylpropionic acid

[0108] 

[0109] ¹H NMR (270 MHz, CDCl₃) δ 1.58 (s, 6H), 4.63 (s, 2H), 5.18 (s, 2H), 6.82 (d, J = 9 Hz, 2H), 7.06 (d, J = 9 Hz, 2H), 7.06-7.11 (m, 1H), 7.21-7.53 (m, 7H), 7.80-7.99 (m, 3H)

Example 29

2-[4-[[N-(Benzoxazol-2-yl)-N-(2-nitrobenzyl)]aminomethyl]phenoxy]-2-methylpropionic acid

[0110] 

[0111] ¹H NMR (270 MHz, CDCl₃) δ 1.59 (s, 6H), 4.77 (s, 2H), 5.11 (s, 2H), 6.87 (d, J = 9 Hz, 2H), 7.00-7.32 (m, 4H), 7.18 (d, J = 9 Hz, 2H), 7.35-7.49 (m, 2H), 7.57 (m, 1H), 8.19 (d, J = 8 Hz, 1H)

Example 41

2-[3-[[N-(Benzoxazol-2-yl)-N-(4-dimethylaminobenzyl)]aminomethyl]phenoxy]-2-methylpropionic acid

[0112] 

[0113] MS (m/z) 459 (M⁺)

Example 46

3-[[N-(Benzoxazol-2-yl)-N-n-heptyl]aminomethyl]phenoxyacetic acid

[0114] 

[0115] MS (m/z) 396 (M⁺)

Example 48

3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxyacetic acid

[0116] 

[0117] MS (m/z) 410 (M⁺)

Example 55

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl]phenoxy]butyric acid

[0118] 

[0119] ¹H NMR (270 MHz, CDCl₃) δ 1.03 (t, J = 7 Hz, 3H), 1.81-2.10 (m, 4H), 2.56 (t, J = 6 Hz, 2H), 3.46 (t, J = 6 Hz, 2H), 4.49 (br.s, 1H) , 4.58 (d, J = 17 Hz, 1H) , 4.65 (d, J = 17 Hz, 1H) , 6.70-6.95 (m, 3H), 6.99 (t, J = 7 Hz, 1H) , 7.07-7.32 (m, 8H), 7.35 (d, J = 8 Hz, 1H)

Example 56

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-(4-chlorophenyl) propyl)] aminomethyl]phenoxy]butyric acid

[0120] 

[0121] ¹H NMR (270 MHz, CDCl₃) δ 1.07 (t, J = 7 Hz, 3H), 1.70-2.05 (m, 4H), 2.50 (t, J = 6 Hz, 2H), 3.42 (t, J = 6 Hz, 2H), 4.53 (br.s, 1H), 4.58 (d, J = 17 Hz, 1H), 4.63 (d, J = 17 Hz, 1H), 6.73-6.83 (m, 3H), 6.93-7.03 (m, 3H), 7.03-7.38 (m, 5H), 7.34 (d, J = 7 Hz, 1H)

Example 59

2-[3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]butyric acid

[0122] 

[0123] ¹H NMR (270 MHz, CDCl₃) δ 0.86 (t, J = 7 Hz, 3H), 1.03 (t, J = 7 Hz, 3H), 1.23 (br.s, 10H), 1.60 (br.s, 2H), 1.88-2.05 (m, 2H), 3.30-3.50 (m, 2H), 4.53 (br.s, 1H), 4.66 (d, J = 16 Hz, 1H), 4.71 (d, J= 16 Hz, 1H) , 6.77-6.87 (m, 3H), 6.93-7.04 (m, 1H) , 7.06-7.26 (m, 3H), 7.32 (d, J = 7 Hz, 1H)

Example 63

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-(4-chlorophenyl)propyl)] aminomethyl] phenoxy] propionic acid

[0124] 

[0125] MS (m/z) 464, 466 (M⁺)

Example 69

2-[3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]propionic acid

[0126] 

[0127] MS (m/z) 424 (M⁺)

Example 70

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl]phenoxy]propionic acid

[0128] 

[0129] MS (M/Z) 430 (M⁺)

Example 74

2-[3-[[N-(Benzoxazol-2-yl)-N-n-propyl]aminomethyl]phenoxy]propionic acid

[0130] 

[0131] MS (m/z) 354 (M⁺)

Production Example 13

Synthesis of tert-butyl 2-[3-[2-(ethoxycarbonyl)ethenyl] phenoxy]-2-methylpropionate

[0132] 

60% Sodium hydride (6.1 g, 0.15 mol) was dissolved in tetrahydrofuran. Subsequently, triethylphosphonoacetate (30.2 mL, 0.15 mol) was added dropwise under ice-cooling. After 30 minutes, tert-butyl 2-(3-formylphenoxy)-2-methylpropionate (33.6 g, 0.13 mol) was added under ice-cooling, the mixture was stirred for one hour. Thereafter, the temperature of the mixture was raised to room temperature, and the mixture was stirred for five hours. An aqueous ammonium chloride solution was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 9/1), whereby the target compound was obtained (39.1 g, 92%).
¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 1.58 (s, 6H), 4.26 (q, J= 7 Hz, 2H), 6.38 (d, J = 16 Hz, 1H), 6.87 (d, J = 8 Hz, 1H), 6.99-7.09 (m, 1H), 7.13 (d, J = 8 Hz, 1H), 7.22-7.26 (m, 1H), 7.60 (d, J = 16 Hz, 1H)

Production Example 14

Synthesis of tert-butyl 2-[3-[2-(ethoxycarbonyl)ethyl]phenoxy]-2-methylpropionate

[0133] 

[0134] tert-Butyl 2-[3-[2-(ethoxycarbonyl) ethenyl] phenoxy]-2-methylpropionate (39.1 g, 0.12 mol) was dissolved in ethanol. Subsequently, 10% palladium in carbon (3.9 g) was added thereto, the mixture was stirred under hydrogen atmosphere overnight at room temperature. The resultant mixture was subjected to filtration by use of Celite, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 20/1), whereby the target compound was obtained (37.1 g, 94%).
¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J = 7 Hz, 3H), 1.44 (s, 9H), 1.55 (s, 6H), 2.58 (t, J= 8 Hz, 2H), 2.88 (t, J = 8 Hz, 2H), 4.13 (q, J = 7Hz, 2H), 6.68 (d, J = 8 Hz, 1H), 6.72 (s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.13 (t, J = 8 Hz, 1H)

Production Example 15

Synthesis of 3-[3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenyl]propionic acid

[0135] 

[0136] tert-Butyl 2-[3-[2-(ethoxycarbonyl) ethyl] phenoxy]-2-methylpropionate (37.1 g, 0.11 mmol) was dissolved in ethanol. Subsequently, aqueous 10% potassium hydroxide solution was added dropwise, and the mixture was stirred overnight at room temperature. The resultant mixture was concentrated under reduced pressure, and then an aqueous 5% potassium hydrogensulfate solution was added thereto. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 3/2), whereby the target compound was obtained (32.0 g, 94%).
¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.56 (s, 6H), 2.65 (t, J = 8 Hz, 2H), 2.90 (t, J = 8 Hz, 2H), 6.68-6.73 (m, 2H), 6.82 (d, J = 8 Hz, 1H), 7.15 (t, J = 8 Hz, 1H)

Production Example 16

Synthesis of tert-butyl 2-[3-(3-hydroxypropyl)phenoxy]-2-methylpropionate

[0137] 

[0138] 3-[3-(1-tert-Butoxycarbonyl-1-methylethoxy)phenyl]propionic acid (10.0 g, 32.4 mmol) was dissolved in tetrahydrofuran (50 mL). Subsequently, triethylamine (3.6 g, 35.6 mmol) was added dropwise thereto. Ethyl chlorocarbonate (3.87 g, 35.6 mmol) was added under ice-cooling, and the mixture was stirred for one hour at room temperature. Sodium borohydride(2.45 g, 64.8 mmol) in tetrahydrofuran-water solution was added dropwise under ice-cooling, and the mixture was stirred for two hours at room temperature. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with diluted hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=7/3), whereby the target compound was obtained (9.8 g (q.)).
¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.60 (s, 6H), 1.61 (br.s, 1H), 1.87 (m, 2H), 2.65 (t, J = 8 Hz, 2H), 3.66 (t, J = 6 Hz, 2H), 6.67 (d, J = 7 Hz, 1H) , 6.72 (s, 1H) , 6.81 (d, J = 7 Hz, 1H) , 7.13 (t, J = 7 Hz, 1H)

Production Example 17

Synthesis of tert-butyl 2-[3-(3-methanesulfonyloxypropyl)phenoxy]-2-methylpropionate

[0139] 

[0140] tert-Butyl 2-[3-(3-hydroxypropyl)phenoxy]-2-methylpropionate (10.1 g, 34.3 mmol) was dissolved in methylene chloride (50 mL). Subsequently, triethylamine (6.94 g, 68.6 mmol) was added thereto. Mesyl chloride (4.71 g, 41.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred for five hours at room temperature. Diluted hydrochloric acid was added thereto, the resultant mixture was extracted with chloroform. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 4/1), whereby the target compound was obtained (7.8 g, 61%).
¹H NMR (900 MHz, CDCl₃) δ 1.44 (s, 9H) , 1. 56 (s, 6H) , 2.05 (quintet, J = 7 Hz, 2H), 2.69 (t, J = 7 Hz, 2H), 2.99 (s, 3H), 4.21 (t, J = 7 Hz, 2H), 6.67-6.72 (m, 2H), 6.79 (t, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H)

Production Example 18

Synthesis of tert-butyl 2-[3-(3-phthalimidopropyl)phenoxy]-2-methylpropionate

[0141] 

[0142] tert-Butyl 2-[3-(3-methanesulfonyloxypropyl)phenoxy]-2-methylpropionate (1.93 g, 5.18 mmol) was dissolved in dimethylformamide (10.0 mL). Subsequently, potassium phthalimide (1.15 g, 6.22 mmol) was added thereto, and the mixture was stirred overnight at 80°C. Water was added thereto, and the resultant mixture was extracted with diethyl ether. The reaction mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 5/1), thereby the target compound was obtained (1.8 g, 82%).
¹H NMR (900 MHz, CDCl₃) δ 1.43 (s, 9H), 1.55 (s, 6H), 2.05 (quintet, J = 8 Hz, 2H), 2.62 (t, J = 8 Hz, 2H), 3.73 (t, J = 8 Hz, 2H), 6.65 (d, J = 8 Hz, 1H) , 6. 71 (s, 1H) , 6.81 (d, J = 8 Hz, 1H) , 7.11 (d, J = 8 Hz, 1H) , 7.69-7.73 (m, 2H), 7.82-7.86 (m, 2H)

Production Example 19

Synthesis of tert-butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropionate

[0143] 

[0144] tert-Butyl 2-[3-(3-phthalimidopropyl)phenoxy]-2-methylpropionate (1.87 g, 4.41 mmol) was dissolved in ethanol (10.0 mL). Subsequently, hydrazine monohydrate (184 mg, 5.74 mmol) was added dropwise, and the mixture was stirred overnight at 80°C. Thereafter, the temperature of the mixture was returned to room temperature, and the mixture was subjected to filtration. The resultant filtrate was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol (saturated with ammonia) = 20/1), whereby the target compound was obtained (560 mg, 43%).
¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.56 (s, 6H), 1.74 (quintet, J = 7 Hz, 2H), 2.59 (t, J = 7 Hz, 2H), 2.71 (t, J = 7 Hz, 2H), 6.66 (dd, J= 8, 2 Hz, 1H), 6.71 (s, 1H) , 6.79 (d, J = 8 Hz, 1H) , 7.12 (d, J = 8 Hz, 1H)

Production Example 20

Synthesis of tert-butyl 2-[3-(3-(N-benzoxazol-2-yl)aminopropyl] phenoxy]-2-methylpropionate

[0145] 

[0146] tert-Butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropionate (167 mg, 0.57 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, diisopropylethylamine (73.6 mg, 0.57 mmol) and then 2-chlorobenzoxazole (96.2 mg, 0.63 mmol) were added dropwise thereto, and the mixture was stirred for four hours at room temperature. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=3/1), whereby the target compound was obtained (173 mg, 74%).
¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.55 (s, 6H), 1.99 (quintet, J = 7 Hz, 2H), 2.67 (t, J = 7 Hz, 2H), 3. 49 (br.s, 2H), 5.46 (br.s, 1H), 6.68 (dd, J = 8, 2 Hz, 1H), 6.73 (br.s, 1H), 6.79 (d, J= 8 Hz, 1H) , 7.01 (td, J = 8, 1 Hz, 1H) , 7.11-7.17 (m, 2H), 7.23 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H)

Production Example 21

Synthesis of tert-butyl 2-[3-[3-[N-(benzoxazol-2-yl)-N-(4-methoxybenzyl)]aminopropyl]phenoxy]-2-methylpropionate

[0147] 

[0148] tert-Butyl 2-[3-[3-(N-benzoxazol-2-yl)aminopropyl]phenoxy]-2-methylpropionate (30 mg, 0.07 mmol) was dissolved in acetonitrile (3.0 mL), and cesium carbonate (47 mg, 0.15 mmol) was added thereto. Subsequently, 4-methoxybenzyl chloride (17.2 mg, 0.11 mmol) was added dropwise, and the mixture was stirred overnight at 70°C. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 5/1), whereby the target compound was obtained (16.5 mg, 43%).

Example 101

Synthesis of 2-[3-[3-[N-(benzoxazol-2-yl)-N-(4-methoxybenzyl)]aminopropyl]phenoxy]-2-methylpropionic acid

[0149] 

[0150] tert-Butyl 2-[3-[3-[N-(benzoxazol-2-yl)-N-(4-methoxybenzyl)]aminopropyl]phenoxyl]-2-methylpropionate (17.2 mg, 0.03 mmol) was dissolved in methylene chloride (1.0 mL). Subsequently, 50% trifluoroacetic acid in methylene chloride solution was added dropwise thereto, and the mixture was stirred for three hours at room temperature. The resultant mixture was subjected to toluene azeotrope and purification by preparative TLC (chloroform/methanol = 20/1), whereby the target compound was obtained (8.7 mg, 61%).
MS (m/z) 474 (M⁺)

[0151] In a manner similar to that described in Example 101, the compounds of Example 114 and Example 121 were synthesized.

Example 114

2-[4-[3-[N-(Benzoxazol-2-yl)-N-ethyl] aminopropyl] phenoxy]-2-methylpropionic acid

[0152] 

[0153] MS (m/z) 382 (M⁺)

Example 121

2-[3-[3-[N-(Benzoxazol-2-yl)-N-(2-butynyl)] aminopropyl] phenoxy]-2-methylpropionic acid

[0154] 

[0155] MS (m/z) 407 (M+1) (FAB)

Production Example 22

Synthesis of 3-(4-hydroxyphenyl)-N-n-propylpropionamide

[0156] 

[0157] 3-(4-Hydroxyphenyl)propionic acid (12.0 g, 72.0 mmol) was dissolved in tetrahydrofuran (20 mL). n-Propylamine (5.1 g, 86.4 mmol) was added dropwise at room temperature. Subsequently, under ice-cooling, solution (20 mL) of WSCI-hydrochloric acid salt (16.5 g, 86.4 mmol) in methylene chloride was slowly added thereto, and the resultant mixture was stirred overnight. Diluted hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol = 50/1), whereby the target compound was obtained (9.7 g, 65%).
¹H NMR (400 MHz, CDCl₃) δ 0.83 (t, J = 7 Hz, 3H), 1.43 (m, 2H), 2. 44 (t, J = 8 Hz, 2H), 2.87 (t, J= 8 Hz, 2H), 3.15 (m, 2H), 5.56 (s, 1H), 6.76 (d, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz, 2H)

Production Example 23

Synthesis of tert-butyl 2-[4-[2-(N-n-propylaminocarbonyl)ethyl]-2-methylpropionate

[0158] 

[0159] 3-(9-Hydroxyphenyl)-N-n-propylpropionamide (9.7 g, 47.0 mmol) was dissolved in acetonitrile (20 mL), and potassium carbonate (22.4 g, 163 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (31.1 g, 140 mmol) was added thereto, and the mixture was stirred overnight at 75°C. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 10/1), whereby the target compound was obtained (9.6 g, 59%).
¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J = 7 Hz, 3H), 1.39-1.48 (m, 2H), 1.45 (s, 9H), 1.54 (s, 6H), 2.92 (t, J = 8 Hz, 2H), 2.89 (t, J = 8 Hz, 2H), 3.16 (m, 2H), 5.32 (br.s, 1H), 6.78 (d, J = 9 Hz, 2H), 7.05 (d, J = 9 Hz, 2H)

Production Example 24

Synthesis of tert-butyl 2-[4-[3-(N-n-propyl) aminopropyl] phenoxy]-2-methylpropionate

[0160] 

tert-Butyl 2-[4-[2-(N-n-propylaminocarbonyl)ethyl] phenoxy]-2-methylpropionate (4.0 g, 11.4 mmol) was dissolved in tetrahydrofuran (10 mL). 1.0M Borane-tetrahydrofuran complex in tetrahydrofuran solution (34.3 mL, 34.3 mmol) was added dropwise, the mixture was stirred for three hours at 50°C. Concentrated hydrochloric acid was added under ice-cooling, the mixture was stirred for three hours at room temperature. Aqueous 80% ethylamine solution was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol = 50/1), whereby the target compound was obtained (2.3 g, 59%).
¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J = 7 Hz, 3H), 1.41-1.56 (m, 2H), 1.44 (s, 9H), 1.54 (s, 6H), 1.80 (quintet, J = 8 Hz, 2H), 2.55-2.60 (m, 4H) 2.63 (t, J = 7 Hz, 2H), 6. 77 (d, J = 8 Hz, 2H), 7.03 (d, J = 8 Hz, 2H)

Production Example 25

Synthesis of tert-butyl 2-[4-[3-[N-(benzoxazol-2-yl) -N-n-propyl] aminopropyl] phenoxy]-2-methylpropionate

[0161] 

[0162] tert-Butyl 2-[4-[3-(N-n-propyl)aminopropyl]phenoxy]-2-methylpropionate (1.8 g, 5.3 mmol) was dissolved in dimethylformamide (5.0 mL), and diisopropylethylamine (1.02 g, 7.95 mmol) was added dropwise thereto. Subsequently, 2-chlorobenzoxazole (977 mg, 6.36 mmol) was added dropwise thereto, the mixture was stirred for two hours at 50°C. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate = 4/1), whereby the target compound was obtained (1.1 g, 46%).
¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J = 7 Hz, 3H), 1.44 (s, 9H), 1.54 (s, 6H), 1.64-1.69 (m, 2H), 1.94-2.4 (m, 2H), 2.63 (t, J = 8 Hz, 2H), 3.45 (t, J = 8 Hz, 2H), 3.54 (t, J = 7 Hz, 2H), 6.79 (d, J = 9 Hz, 2H), 6.98 (t, J= 8 Hz, 1H), 7.05 (d, J = 9 Hz, 2H), 7.14 (t, J= 8 Hz, 1H), 7.22 (d, J = 8 Hz, 1H) , 7.34 (d, J = 8 Hz, 1H)

Example 132

Synthesis of 2-[4-[3-[N-(Benzoxazol-2-yl)-N-n-propyl] aminopropyl] phenoxy]-2-methylpropionic acid

[0163] 

[0164] tert-Butyl 2-[4-[3-[N-(benzoxazol-2-yl)-N-n-propyl] aminopropyl] phenoxy]-2-methylpropionate (1.1 g, 2.43 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 50% trifuloroacetic acid in methylene chloride solution (3.0 g) was added dropwise thereto, and the mixture was stirred for three hours at room temperature. The resultant mixture was subjected to concentration under reduced pressure, toluene azeotrope, and purification by silica gel chromatography (chloroform/methanol = 50/1), whereby the target compound was obtained (1.0 g, q.). ¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J = 7 Hz, 3H), 1.59 (s, 6H), 1.63-1.69 (m, 2H), 1.96 (quintet, J = 7 Hz, 2H), 2.59 (t, J = 7 Hz, 2H), 3.44 (t, J= 7 Hz, 2H), 3.56 (t, J = 7 Hz, 2H), 6.84 (d, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz, 2H), 7.05 (t, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.25 (d, J = 8 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 11.9 (br.s, 1H)

Synthesis of sodium 2-[4-[3-[N-(benzoxazol-2-yl)-N-n-propyl] aminopropyl] phenoxy]-2-methylpropionate

[0165] 

2-[4-[3-[N-(Benzoxazol-2-yl)-N-n-propyl]aminopropyl] phenoxy]-2-methylpropionic acid (1.0 g, 2.6 mmol) was dissolved in methanol. Subsequently, sodium methoxide (142 mg, 2.6 mmol) in methanol was added thereto at room temperature, and the mixture was stirred for one hour. The resultant mixture was concentrated under reduced pressure, and hexane was added to the resultant concentrate, to thereby precipitate a solid. The thus-obtained solid was purified, whereby a white amorphous powder was obtained (820 mg, 75%).
¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J = 7 Hz, 3H), 1.29 (s, 6H), 1.59-1.69 (m, 2H), 1.82-1.90 (m, 2H), 2.54 (t, J = 7 Hz, 2H), 3.41 (t, J = 7 Hz, 2H), 3.49 (t, J = 7 Hz, 2H), 6.70 (d, J = 8 Hz, 2H), 6.94 (d, J = 8 Hz, 2H), 6.95 (t, J = 8 Hz, 1H), 7.11 (t, J = 8 Hz, 1H) , 7.20 (d, J = 8 Hz, 1H) , 7.32 (d, J = 8 Hz, 1H)

[0166] In a manner similar to that described in Example 132, the compound of Example 133 was synthesized.

Example 133

2-[4-[3-[N-(Benzoxazol-2-yl)-N-isopropyl]aminopropyl] phenoxy]-2-methylpropionic acid

[0167] 

[0168] ¹H NMR (400 MHz, CDCl₃) δ 1.28 (d, J = 7 Hz, 6H), 1.56 (s, 6H), 1.96-2.10 (m, 2H), 2.65 (t, J = 8 Hz, 2H), 3.51 (t, J = 8 Hz, 2H), 4.46 (septet, J = 7 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 7.16 (t, J = 8 Hz, 1H) , 7.25-7.31 (m, 2H), 7.55 (d, J = 8 Hz, 1H), 11.2 (br.s, 1H) Production Example 26

Synthesis of tert-butyl 2-(3-methoxycarbonylphenoxy)-2-methylpropionate

[0169] 

[0170] Methyl 3-hydroxybenzoate (17.05 g, 0.112 mol) was dissolved in dimethylformamide (100 mL). Subsequently, potassium carbonate (20.12 g, 0.145 mol) and then tert-butyl 2-bromoisobutyrate (50.00 g, 0.224 mol) were added thereto, and the mixture was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the concentrate. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ ethyl acetate = 10/1), whereby a colorless oil was obtained (17.03 g, 57.80 mmol, 51.6%).
¹H-NMR (270 MHz, CDCl₃) δ: 1.46 (s, 9H), 1.58 (s, 6H), 3.89 (s, 3H), 6.83 (dd, J = 8, 3 Hz, 1H), 7. 30 (t, J = 8 Hz, 1H), 7.52 (dd, J = 3, 2 Hz, 1H), 7.65 (dt, J = 8, 1 Hz, 1H).

Production Example 27

Synthesis of 3-(1-tert-butoxycarbonyl-1-methylethoxy) benzoic acid

[0171] 

[0172] tert-Butyl 2-(3-methoxycarbonylphenoxy)-2-methylpropionate (17.03 g, 57.80 mmol) was dissolved in methanol (80 mL). Subsequently, an aqueous 3M sodium hydroxide solution (40 mL) was added thereto, and the mixture was stirred for three hours at room temperature. After completion of reaction, the mixture was acidified with hydrochloric acid under ice-cooling, to thereby precipitate colorless crystals. The crystals were subjected to filtration, thorough washing with water, and drying under reduced pressure, whereby colorless crystals were obtained (14.92 g, 53.22 mmol, 92.0%).
¹H-NMR (270 MHz, CDCl₃) δ: 1.46 (s, 9H), 1.60 (s, 6H), 7.13 (dd, J = 8,3 Hz, 1H) , 7.35 (t, J= 8 Hz, 1H) , 7.58 (s, 1H), 7.73 (d, J = 8 Hz, 1H)

Production Example 28

Synthesis of tert-butyl 2-(3-allyloxycarbonylphenoxy)-2-methylpropionate

[0173] 

[0174] 3-(1-tert-Butoxycarbonyl-1-methylethoxy) benzoic acid (14.92 g, 53.22 mmol) was dissolved in acetonitrile (60 mL). Subsequently, diisopropylamine (8.25 g, 63.87 mmol) was added thereto. Thereafter, allyl bromide (12.87 g, 106.45 mmol) was added dropwise, and the mixture was stirred for five hours at room temperature. Ethyl acetate was added for extraction. Washing was performed sequentially with water and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate = 10/1), whereby a colorless oil was obtained (11.59 g, 36.19 mmol, 67.9%).
¹H-NMR (270 MHz, CDCl₃) δ: 1.45 (s, 9H), 1.59 (s, 6H),4.80 (d, J = 6 Hz, 2H), 5.28 (d, J= 11 Hz, 1H), 5.39 (d, J= 17 Hz, 1H), 5.97-6.05 (m, 1H), 7. 07 (dd, J = 8, 3 Hz, 1H) , 7. 31 (t, J = 8 Hz, 1H), 7.54 (s, 1H) , 7.68 (d, J= 8 Hz, 1H) Production Example 29

Synthesis of 2-(3-allyloxycarbonylphenoxy)-2-methylpropionic acid

[0175] 

[0176] tert-Butyl 2-(3-allyloxycarbonylphenoxy)-2-methylpropionate (11.59 g, 36.19 mmol) was dissolved in dichloromethane (20 mL). Subsequently, trifuloroacetic acid (40 mL) was added at room temperature, and the mixture was stirred for three hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the concentrate. The resultant mixture was concentrated again under reduced pressure. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol = 10/1), whereby a yellow oil was obtained (8.30 g, 31.41 mmol, 86.7%).
¹H-NMR (270 MHz, CDCl₃) δ: 1.64 (s, 6H),4.80 (d, J = 6 Hz, 2H), 5.28 (d, J = 10 Hz, 1H) , 5.40 (d, J = 17 Hz, 1H), 5.97-6.05 (m, 1H), 7. 07 (dd, J = 8, 3 Hz, 1H) , 7. 31 (t, J = 8 Hz, 1H), 7.54 (s, 1H), 7.68 (d, J = 8 Hz, 1H)

Production Example 30

Synthesis of 2-(3-allyloxycarbonylphenoxy)-2-methylpropionic acid Wang resin ester

[0177] 

[0178] 2-(3-Allyloxycarbonylphenoxy)-2-methylpropionic acid (8.30 g, 31.41 mmol) and triphenylphosphine (21.96 g, 83.75 mmol) were dissolved in tetrahydrofuran (200 mL). Thereafter, a Wang resin was added to the resultant mixture (1.1 mmol/g, 200-400 mesh, 19.03 g, 20.94 mmol) for swelling the resin. Subsequently, under argon atmosphere and under ice-cooling, diethyl azodicarboxylate (DEAD, 40% in toluene, 36.29 mL, 83.75 mmol) was added dropwise. After one hour, the temperature of the mixture was returned to room temperature, and the mixture was stirred overnight. The resin was collected through filtration and transferred to an Erlenmeyer flask, followed by addition of dimethylformamide and stirring for 15 minutes. The same procedure was performed three times. Thereafter, by use of dichloromethane, the same procedure was repeated. The resultant mixture was washed three times with methanol, then twice with diethyl ether, followed by drying under reduced pressure. The resin was allowed to swell in dichloromethane (200 mL). Diisopropylamine (5.95 g, 46.06 mmol) was added, and subsequently acetic anhydride (4.27 g, 41.88 mmol) was added. The mixture was stirred overnight at room temperature under argon atmosphere. Washing was performed three times with dichloromethane and with methanol, followed by drying under reduced pressure at room temperature. (23.36 g, increased in an amount of 4.33 g). The resin (100 mg) was treated with 50% trifuloroacetic acid in dichloromethane, subjected to toluene azeotrope, and dried sufficiently. From the thus-obtained 2-(3-allyloxycarbonylphenoxy)-2-methylpropionic acid (23 mg, 0.087 mmol), the amount of the compound incorporated into the resin was estimated to be 0.87 mmol/g (percent incorporation: 79.1%).

Production Example 31

Synthesis of 3-[1-(Wang resin-oxycarbonyl)-1-methylethoxy] benzoic acid

[0179] 

[0180] Triphenylphosphine (4.57 g, 17.43 mmol) was dissolved in tetrahydrofuran (200 mL). The resin prepared in Production Example 30 (22.26 g, 19.37 mmol) was added for swelling the resin. Subsequently, under argon atmosphere, tetrakis(triphenylphosphine)palladium (6.71 g, 5.81 mmol) was added thereto, and the resultant mixture was made homogeneous. Thereafter, piperidine (49.47 g, 580.98 mmol) was added thereto, and the resultant mixture was stirred overnight at room temperature. The resin was collected through filtration and transferred to an Erlenmeyer flask, followed by addition of dimethylformamide and stirring for 15 minutes. The same procedure was performed three times. Thereafter, by use of dichloromethane, the same procedure was repeated. The resultant mixture was washed three times with methanol, followed by drying under reduced pressure at room temperature, whereby the target compound was obtained (22.10 g).

Production Example 32

Synthesis of 2-[3-(N-cyclohexylmethylaminocarbonyl)phenoxy]-2-methylpropionic acid Wang resin ester

[0181] 

[0182] The resin prepared in Production Example 31 (0.87 mmol/g, 300 mg, 0.261 mmol) was added to dimethylformamide (3 mL), to thereby cause swelling of the resin. Thereafter, HOBt (353 mg, 2.610 mmol), cyclohexylmethylamine (2.610 mmol), and diisopropylethylamine (337 mg, 2.610 mmol) were added. Lastly, diisopropylcarbodiimide [DIC (329 mg, 2.610 mmol)] was added, and the resultant mixture was stirred overnight at room temperature. The reaction mixture was sequentially washed with dimethylformamide (three times), dichloromethane (three times), methanol (three times), and diethyl ether (three times), for five minutes each time.

Production Example 33

Synthesis of 2-[3-[(N-cyclohexylmethyl) aminomethyl]phenoxy] -2-methylpropionic acid Wang resin ester

[0183] 

[0184] Tetrahydrofuran (1 mL) and then borane-tetrahydrofuran complex in tetrahydrofuran solution [BH₃-THF in THF (1.08 M, 6 mL)] were added to the resin prepared in Production Example 32, and the resultant mixture was stirred under nitrogen atmosphere for 2.5 hours at 50°C. The temperature of the mixture was returned to room temperature. Methanol was added to the reaction mixture, and the mixture was washed three times. Thereafter, the resultant mixture was sequentially washed with methanol (three times), dimethylformamide (three times), dichloromethane (three times), methanol (three times), diethyl ether (three times), for five minutes each time.

Production Example 34

Synthesis of 2-[3-[[N-(benzoxazol-2-yl)-N-cyclohexylmethyl] aminomethyl] phenoxy]-2-methylpropionic acid Wang resin ester

[0185] 

[0186] Dimethylformamide (4 mL) and then diisopropylethylamine (337 mg, 2.610 mmol) were added to the resin prepared in Production Example 33. Subsequently, 2-chlorobenzoxazole (801 mg, 5.22 mmol) was added thereto, the mixture was stirred overnight at 50°C. The resultant mixture was sequentially washed with dimethylformamide (three times), dichloromethane (three times), methanol (three times), diethyl ether (three times), for five minutes each time.

Example 134

Synthesis of 2-[3-[[N-(benzoxazol-2-yl)-N-(cyclohexylmethyl)] aminomethyl]phenoxy]-2-methylpropionic acid

[0187] 

[0188] 50% Trifuloroacetic acid in dichloromethane (5 mL) was added to the resin prepared in Production Example 34, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was collected. Subsequently, dichloromethane (5 mL) was added thereto, and the resultant mixture was stirred for five minutes. Thereafter, the mixture was subjected to concentration under reduced pressure, toluene azeotrope, thorough drying, and purification by preparative TLC (silica gel, chloroform/methanol = 10/1), whereby the target compound was obtained (18.7% from Production Example 30).
MS (m/z) 422 (M⁺)

[0189] In a manner similar to that described in Example 134, the compound of Example 135 was synthesized.

Example 135

2-[3-[[N-(Benzoxazol-2-yl)-N-(naphth-1-ylmethyl)] aminomethyl]phenoxy]-2-methylpropionic acid

[0190] 

[0191] MS (m/z) 466 (M⁺)

Production Example 35

Synthesis of 3-(2-methoxyphenyl)propionamide

[0192] 

[0193] 3-(2-methoxyphenyl)propionic acid (9.0 g, 49.9 mmol) was dissolved in acetonitrile (10 mL). Subsequently, pyridine (3.54 g, 44.9 mmol) and di-tert-butyl dicarbonate [Boc₂O (16.3 g, 74.85 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (5.92 g, 74.9 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 36 without purification.

Production Example 36

Synthesis of 3-(2-hydroxyphenyl)propionamide

[0194] 

[0195] The compound prepared in Production Example 35 was dissolved in methylene chloride. Subsequently, 1.0M boron tribromide in methylene chloride solution (78.8 mL, 78.8 mmol) was added dropwise under ice-cooling. The temperature of the mixture was allowed to room temperature, followed by stirring for three hours. Water was added thereto, and the mixture was extracted with chloroform, followed by washing with saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by column chromatography (chloroform/methanol = 20/1), whereby the target compound was obtained (6.01 g, 92%).
¹H NMR (400 MHz, CDCl₃) δ 2.64 (t, J = 6 Hz, 2H), 2.90 (t, J = 6 Hz, 2H), 5.67 (br.s, 1H), 5.88 (br.s, 1H), 6.84 (t, J= 7 Hz, 1H) , 6.89 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 7.11 (t, J = 7 Hz, 1H), 8.50 (br.s, 1H)

Production Example 37

Synthesis of tert-butyl 2-[2-(2-aminocarbonylethyl) phenoxy]-2-methylpropionate

[0196] 

[0197] 3-(2-Hydroxyphenyl)propionamide (5.6 g, 33.9 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (18.7 g, 135 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (30.3 g, 135 mmol) was added, and the mixture was stirred at 80°C. After completion of reaction, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol = 40/1), whereby the target compound was obtained (2.67 g, 26%).

Production Example 38

Synthesis of tert-butyl 2-[2-(3-aminopropyl)phenoxy]-2-methylpropionate

[0198] 

[0199] tert-Butyl 2-[2-(2-aminocarbonylethyl) phenoxy]-2-methylpropionate (2.7 g, 8.68 mmol) was dissolved in tetrahydrofuran (5mL). Subsequently, under nitrogen atmosphere, borane-tetrahydrofuran complex in tetrahydrofuran solution [1-OM BH₃-THF in THF (26.1 mL, 26.1 mmol)] was added thereto, the mixture was stirred for three hours at 50°C. Thereafter, concentrated hydrochloric acid was gradually added thereto at 0°C. The resultant mixture was stirred for one hour at room temperature and made basic with an aqueous ethylamine solution. Ethyl acetate was added thereto. The mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol = 30/1), whereby the target compound was obtained (1.44 g, 4.91 mmol, 57%).
¹H NMR (400 MHz, CDCl₃) δ 1.41 (s, 9H), 1.59 (s, 6H), 1.75 (quintet, J = 7 Hz, 2H) , 2. 66 (t, J = 7 Hz, 2H) , 2.71 (t, J = 7 Hz, 2H), 6.68 (d, J = 8 Hz, 1H) , 6.87 (t, J = 7 Hz, 1H) , 7.04 (t, J = 8 Hz, 1H), 7.12 (d, J = 7 Hz, 1H)

Production Example 39

Synthesis of tert-butyl 2-[2-[3-(N-benzoxazol-2-yl) aminopropyl] phenoxy]-2-methylpropionate

[0200] 

[0201] tert-Butyl 2-[2-(3-aminopropyl)phenoxy]-2-methylpropionate (1.44 g, 4.9 mmol) was dissolved in tetrahydrofuran (5mL). Subsequently, diisopropylethylamine (762 mg, 5.9 mmol) and then 2-chlorobenzoxazole (904 mg, 5.9 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate was added thereto. The resultant mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate = 6/1), whereby the target compound was obtained (2.03 g, q.).
¹H NMR (400 MHz, CDCl₃) δ 1.42 (s, 9H), 1.64 (s, 6H), 1.99 (quintet, J = 7 Hz, 2H) , 2.77 (t, J = 7 Hz, 2H) , 3.39-3.44 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 6.90 (t, J = 8 Hz, 1H), 7.00 (t, J = 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.12-7.16 (m, 2H), 7.20 (d, J = 8 Hz, 1H) , 7.35 (d, J = 8 Hz, 1H)

Production Example 40

Synthesis of tert-butyl 2-[2-[3-[N-(benzoxazol-2-yl)-N-n-octyl] aminopropyl] phenoxy]-2-methylpropionate

[0202] 

[0203] tert-Butyl 2-[2-[3-(N-benzoxazol-2-yl)aminopropyl] phenoxy]-2-methylpropionate (120 mg, 0.29 mmol) was dissolved in acetonitrile (2 mL). Subsequently, cesium carbonate (206 mg, 0.584 mmol) and n-octyl bromide (112 mg, 0.58 mmol) were added thereto, and the mixture was stirred overnight at 80°C. The temperature of the mixture was returned to room temperature, and ethyl acetate was added. The resultant mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, purification by silica gel column chromatography (n-hexane/ethyl acetate = 4/1), whereby the target compound was obtained (124 mg, 0.24 mmol, 82%).

Example 155

Synthesis of 2-[2-[3-[N-(benzoxazol-2-yl)-N-n-octyl] aminopropyl]phenoxy]-2-methylpropionic acid

[0204] 

[0205] tert-Butyl 2-[2-[3-[N-(benzoxazol-2-yl)-N-n-octyl] aminopropyl]phenoxy]-2-methylpropionate (124 mg, 0.24 mmol) was dissolved in methylene chloride (1 mL). Subsequently, 50% trifuloroacetic acid in methylene chloride solution was added thereto, and the mixture was stirred for three hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant concentrate was subjected to toluene azeotrope. Thereafter, chloroform was added thereto, followed by washing sequentially with water and saturated brine, and drying over sodium sulfate. The resultant mixture was subjected to concentration under reduced pressure and purification by preparative TLC (silica gel, chloroform/methanol = 20/1), whereby the target compound was obtained (79.7 mg, 0.17 mmol, 71%).
MS (m/z) 466 (M⁺)

Test Example 1

[0206] PPAR activating effect of the compounds falling within the scope of the present invention represented by formula (1) and, as comparative compounds, the compounds as recited in WO 02/46176 (hereinafter, referred to as compounds A, B and C) were determined through the following method (Proc. Natl. Acad. Sci., 92, pp. 7297-7301, 1995; Journal of Biological Chemistry, 269, pp. 31012-31018, 1994; and Proc. Natl. Acad. Sci, 98, pp. 5306-5311, 2001).

a. Method of determination

Transfection assay

[0207] Every transfection assays were performed on COS cells, which are cell strains originating from the kidney of Cercopithecus aethiops, by using lipofectamine procedure. COS cells were cultured under CO₂ (5%) by use of a DMEM medium containing 10% fetal bovine serum, glutamic acid, and an antibiotic.

[0208] pSG5hPPARα, pSG5hPPARγ, or pcDNA3hPPARδ was used as a wild-type human PPAR expression vector. Firefly luciferase reporter plasmid containing 6-repeated PPAR responsive element present in a human apoAII promoter was used as a reporter vector. A β-galactosidase expression vector was employed as an internal standard.

[0209] Transiently transfected cells were incubated with or without compound. And after 16 hours, luciferase activity and β-galactosidase of cell lysate were determined.

[0210] In the present test, each compound was dissolved in and diluted with dimethyl sulfoxide (DMSO), and the DMSO concentration of the DMEM medium (containing 0.2% serum) was adjusted to 0.1% upon treatment of cells.

[0211] Also in the present test, dimethylsulfoxide (DMSO) was used to dissolve and dilute the compounds. The treatment of the cells was performed by use of the DMEM medium (containing 0.2% serum) with DMSO such that the DMSO content is adjusted to 0.1%. As poitive control compounds, WY 14643, troglitazone (Journal of Medicinal Chemistry, 43, pp. 527-550, 2000), and GW 501516 (Proc. Natl. Acad. Sci., 98, pp. 5306-5311, 2001) were used with respect to PPARα, PPARγ, and PPARδ, respectively.

b. Results

[0212] Table 1 shows agonist activity (to hPPARα, hPPARγ, hPPARδ) of the compounds of the present invention.

Table 1

hPPAR; EC50 (µM)
Example No.	α	γ	δ
1	0.01	0.2	>10
6	0.01	0.2	>10
12	0.003	0.1	0.5
29	0.1	>10	>10
41	0.01	0.2	1.8
46	0.01	0.4	1.1
48	0.01	0.7	4.5
55	0.002	0.1	0.6
56	0.001	0.1	1.0
59	0.003	0.1	>10
63	0.002	0.1	0.9
69	0.0003	0.2	>10
70	0.001	0.4	>10
74	0.1	>10	>10
114	0.01	0.4	>10
121 .	0.004	0.1	>10
132	0.03	2.0	>10
133	0.01	0.3	3.0
135	0.01	>10	>10
155	0.01	0.5	0.3
Compound A	0.01	0.5	0.1
Compound B	0.01	0.1	0.5
Compound C	>10	>10	>10
WY 14643	1.5
troglitazone		0.1
GW 501516			0.5

[0213] Activation factors of Compoud of Example 1 Compouds A, B and C with respect to each isoform of PPARs at EC50 for activating hPPARα and at the corresponding 10-time concentration are summarized in Figs. 1 to 4. The activation factor is defined as a ratio to control value, which is the activity obtained when treating the solvent (DMSO) not containing the compounds. The compound of Example 1 exhibited activation to hPPARα at hPPARα activation EC₅₀ value and at the 10-times of EC₅₀ value, while the compound of Example 1 did not activate hPPARγ and hPPARδ.

[0214] In contrast, compounds A and B activated not only hPPARα but also hPPARδ at 10-fold concentration of hPPARα activation EC₅₀ value.

[0215] Compound C hardly activated all hPPAR even at concentration of 10µM, which is higher than hPPARα activation EC₅₀ value of other compounds.

[0216] As is clear from the results, the compounds of the present invention exert PPARα-selective activation effect.

Industrial Applicability

[0217] The compound of the present invention exerts an effect of selectively activating PPARα among other PPARs, and is usefully employed as a drug for preventing and/or treating, without accompanying obesity or increase in body weight, diseases including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.

Claims

1. A compound selected from among the following compounds:

2-[4-[[N-(benzoxazol-2-yl)-N-(naphth-1-ylmethyl)]-aminomethyl] phenoxy]-2-methylpropionic acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-phenylpropyl)] aminomethyl] phenoxy] butyric acid,

2- [3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophenyl)propyl)]-aminomethyl] phenoxy] butyric acid,

2-[3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]-butyric acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophenyl)propyl)]-aminomethyl] phenoxy] propionic acid,

2- [3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminomethyl] phenoxy]-propionic acid,

2-[3-[[N-(benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl)-phenoxy] propionic acid,

2-[3-[3-[N-(benzoxazol-2-yl)-N-(2-butynyl)]aminopropyl]-phenoxy]-2-methylpropionic acid,

and a salt thereof.

2. A agent for selectively activating PPARα, comprising, as an active component, the compound or the salt thereof recited in claim 1.

Ansprüche

1. Verbindung ausgewählt aus den folgenden Verbindungen:

2-[4-[[N-(Benzoxazol-2-yl)-N-(naphth-1-ylmethyl)]-aminomethyl]phenoxy]-2-methylpropionsäure,

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl] phenoxy]butansäure,

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-(4-chlorphenyl)propyl)]-aminomethyl]phenoxy]butansäure,

2-[3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]-butansäure,

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-(4-chlorphenyl)propyl)]-aminomethyl]phenoxy]propionic acid,

2-[3-[[N-(Benzoxazol-2-yl)-N-n-octyl]aminomethyl]phenoxy]-propionsäure,

2-[3-[[N-(Benzoxazol-2-yl)-N-(3-phenylpropyl)]aminomethyl]-phenoxy]propionsäure,

2-[3-[3-[N-(Benzoxazol-2-yl)-N-(2-butynyl)]aminopropyl]-phenoxy]-2-methylpropionsäure,

und einem Salz derselben.

2. Mittel zum selektiven Aktivieren von PPARα, umfassend als aktive Komponente die Verbindung oder deren Salz gemäß Anspruch 1.

Revendications

1. Composé choisi parmi les composés suivants:

acide 2-[4-[[N-(benzoxazol-2-yl)-N-(napht-1-yl-méthyl)]aminométhyl]phénoxy]-2-méthylpropionique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-(3-phénylpropyl)]-aminométhyl]phénoxy]butyrique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophényl)propyl)]aminométhyl]phénoxy]butyrique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminométhyl]phénoxy]butyrique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-chlorophényl)propyl)]aminométhyl]phénoxy]propionique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-n-octyl]aminométhyl]phénoxy]propionique,

acide 2-[3-[[N-(benzoxazol-2-yl)-N-(3-phénylpropyl)]-aminométhyl]phénoxy]propionique,

acide 2-[3-[3-[N-(benzoxazol-2-yl)-N-(2-butynyl)]-aminopropyl]phénoxy]-2-méthylpropionique,

et leurs sels.

2. Agent pour activer sélectivement PPARα, comprenant, à titre de composant actif, le composé ou sel indiqué dans la revendication 1.

Drawing